(Adapted from Applicant's Abstract) This proposal is strongly based on the previous scientific achievements of this group and represents the most integrated and interactive proposal that the investigators have ever put together. The basic research projects: The first project build on the extensive experience on transgenic mice to solve the problem of organ damage in this disease. The use of the state-of-the-art BOLD MRI, will greatly contribute to the effort. The next project will generate and analyze the structural and functional properties of hybrid interspecies Hbs with ground break semi-synthesis techniques, to generate a super anti- sickling globin that could eventually be useful for gene therapy. In addition, the project will contribute to complete the understanding of the structure of the polymer of deoxyHbs. Dr. Kaul's project will use in vivo techniques to study, at the molecular level, SS cell adhesion to small venules and the abnormalities in the vascular response to oxygen in transgenic mice expression HbS. Dr. Nagel's project involves a molecular analysis of the cellular abnormalities induced by HbC, using advanced crystal growth and coring techniques and the generation of HbC and human K:C1 transgenic mice, to understand volume regulation in CC/SC cells. Dr. Schwart'z project is based on the cloning of a novel C1-channel that is volume sensitive and in the cloning of K:C1 co-transport in human erythroid cells, to understand the molecular basis of volume regulation in SS cells. Dr. Bouhassira's project is based on a new technique which will permit the incorporation of large constructs in predetermined sites of the genome, to study the molecular basis of the function of the LCR and HbF expression during erythropoietic stress. There are two clinical research projects: One in which the genetic and metabolic basis for pain and its management will be studied; and one in which the novel BOLD-MRI technique will be applied, for the first time, to the study of patients with sickle cell anemia. Finally, the investigators have succeeded in transferring most of the costs of the Clinical facility to the Montefiore Medical Center, allowing the new Clinical Core to concentrate on clinical research. The investigators consider this event a strong validation of Dr. Benjamin's organization of the first Day Hospital and pain management effort among the Centers.